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Chronobiology of Aging: A Mini-Review.Cornelissen G, Otsuka K.Gerontology. 2016 Oct 22. [Epub ahead of print]PMID: 27771728Free ArticleAbstracthttp://www.karger.com/Article/FullText/450945Aging is generally associated with weakening of the circadian system. The circadian amplitude is reduced and the circadian acrophase becomes more labile, tending to occur earlier with advancing age. As originally noted by Franz Halberg, similar features are observed in the experimental laboratory after bilateral lesioning of the suprachiasmatic nuclei, suggesting the involvement of clock genes in the aging process as they are in various disease conditions. Recent work has been shedding light on underlying pathways involved in the aging process, with the promise of interventions to extend healthy life spans. Caloric restriction, which is consistently and reproducibly associated with prolonging life in different animal models, is associated with an increased circadian amplitude. These results indicate the critical importance of chronobiology in dealing with problems of aging, from the circadian clock machinery orchestrating metabolism to the development of geroprotectors. The quantitative estimation of circadian rhythm characteristics interpreted in the light of time-specified reference values helps (1) to distinguish effects of natural healthy aging from those associated with disease and predisease; (2) to detect alterations in rhythm characteristics as markers of increased risk before there is overt disease; and (3) to individually optimize by timing prophylactic and/or therapeutic interventions aimed at restoring a disturbed circadian system and/or enhancing a healthy life span. Mapping changes in amplitude and/or acrophase that may overshadow any change in average value also avoids drawing spurious conclusions resulting from data collected at a fixed clock hour. Timely risk detection combined with treatment optimization by timing (chronotherapy) is the goal of several ongoing comprehensive community-based studies focusing on the well-being of the elderly, so that longevity is not achieved at the cost of a reduced quality of life.

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[The below paper is not pdf-availed.]Resveratrol and Lifespan in Model Organisms.Pallauf K, Rimbacha G, Ruppa PM, China D, Wolf I.Curr Med Chem. 2016 Oct 24. [Epub ahead of print]PMID: 27781945AbstractBACKGROUND:Resveratrol may possess life-prolonging and health-benefitting properties, some of which may resemble the effect of caloric restriction (CR). CR appears to prolong the lifespan of model organisms in some studies and may benefit human health. However, for humans, restricting food intake for an extended period of time seems impracticable and substances imitating the beneficial effects of CR without having to reduce food intake could improve health in an aging and overweight population.METHODS:We have reviewed the literature studying the influence of resveratrol on the lifespan of model organisms including yeast, flies, worms, and rodents. We summarize the in vivo findings, describe modulations of molecular targets and gene expression observed in-vivo and in-vitro, and discuss how these changes may contribute to lifespan extension. Data from clinical studies are summarized to provide an insight about the potential of resveratrol supplementation in humans.RESULTS:Resveratrol supplementation has been shown to prolong lifespan in approximately 60% of the conducted studies in model organisms. However, current literature is contradictory, indicating that the lifespan effects of resveratrol vary strongly depending on the model organism. While worms and killifish seemed very responsive to resveratrol, resveratrol failed to affect lifespan in the majority of the studies conducted in flies and mice. Furthermore, factors such as dose, gender, genetic background and diet composition may contribute to the high variance in the observed effects.CONCLUSION:It remains inconclusive whether resveratrol is indeed a CR mimetic and possesses life-prolonging properties. The limited bioavailability of resveratrol may further impede its potential effects.

Effect of energy restriction and physical exercise intervention on phenotypic flexibility as examined by transcriptomics analyses of mRNA from adipose tissue and whole body magnetic resonance imaging.Lee S, Norheim F, Langleite TM, Noreng HJ, Storås TH, Afman LA, Frost G, Bell JD, Thomas EL, Kolnes KJ, Tangen DS, Stadheim HK, Gilfillan GD, Gulseth HL, Birkeland KI, Jensen J, Drevon CA, Holen T; NutriTech Consortium..Physiol Rep. 2016 Nov;4(21). pii: e13019.PMID: 27821717Free Articlehttp://physreports.physiology.org/content/4/21/e13019.longAbstractOverweight and obesity lead to changes in adipose tissue such as inflammation and reduced insulin sensitivity. The aim of this study was to assess how altered energy balance by reduced food intake or enhanced physical activity affect these processes. We studied sedentary subjects with overweight/obesity in two intervention studies, each lasting 12 weeks affecting energy balance either by energy restriction (~20% reduced intake of energy from food) in one group, or by enhanced energy expenditure due to physical exercise (combined endurance- and strength-training) in the other group. We monitored mRNA expression by microarray and mRNA sequencing from adipose tissue biopsies. We also measured several plasma parameters as well as fat distribution with magnetic resonance imaging and spectroscopy. Comparison of microarray and mRNA sequencing showed strong correlations, which were also confirmed using RT-PCR In the energy restricted subjects (body weight reduced by 5% during a 12 weeks intervention), there were clear signs of enhanced lipolysis as monitored by mRNA in adipose tissue as well as plasma concentration of free-fatty acids. This increase was strongly related to increased expression of markers for M1-like macrophages in adipose tissue. In the exercising subjects (glucose infusion rate increased by 29% during a 12-week intervention), there was a marked reduction in the expression of markers of M2-like macrophages and T cells, suggesting that physical exercise was especially important for reducing inflammation in adipose tissue with insignificant reduction in total body weight. Our data indicate that energy restriction and physical exercise affect energy-related pathways as well as inflammatory processes in different ways, probably related to macrophages in adipose tissue.

Nuclear receptor PPARγ has been proven to affect metabolism in multiple tissues, and has received considerable attention for its involvement in colon cancer and inflammatory disease. However, its role in intestinal metabolism has been largely ignored. To investigate this potential aspect of PPARγ function, we submitted intestinal epithelium-specific PPARγ knockout mice (iePPARγKO) to a two-week period of 25% caloric restriction (CR), following which iePPARγKO mice retained more fat than their wild type littermates. In attempting to explain this discrepancy, we analysed the liver, skeletal muscle, intestinal lipid trafficking, and the microbiome, none of which appeared to contribute to the adiposity phenotype. Interestingly, under conditions of CR, iePPARγKO mice failed to activate their sympathetic nervous system (SNS) and increase CR-specific locomotor activity. These KO mice also manifested a defective control of their body temperature, which was overly reduced. Furthermore, the white adipose tissue of iePPARγKO CR mice showed lower levels of both hormone-sensitive lipase, and its phosphorylated form. This would result from impaired SNS signalling and possibly cause reduced lipolysis. We conclude that intestinal epithelium PPARγ plays an essential role in increasing SNS activity under CR conditions, thereby contributing to energy mobilization during metabolically stressful episodes.

Optimising training and performance through nutrition strategies is central to supporting elite sportspeople, much of which has focussed on manipulating the relative intake of carbohydrate and fat and their contributions as fuels for energy provision. The ketone bodies, namely acetoacetate, acetone, and β-hydroxybutyrate (βHB), are produced in the liver during conditions of reduced carbohydrate availability and serve as an alternative fuel source for peripheral tissues including brain, heart and skeletal muscle. Ketone bodies are oxidised as a fuel source during exercise, are markedly elevated during the post-exercise recovery period, and the ability to utilise ketone bodies is higher in exercise-trained skeletal muscle. The metabolic actions of ketone bodies can alter fuel selection through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. Moreover, ketone bodies can act as signalling metabolites with βHB acting as an inhibitor of histone deacetylases, an important regulator of the adaptive response to exercise in skeletal muscle. Recent development of ketone esters facilitates acute ingestion of βHB that results in nutritional ketosis without necessitating restrictive dietary practices. Initial reports suggest this strategy alters the metabolic response to exercise and improves exercise performance, while other lines of evidence suggest roles in recovery from exercise. The present review focuses on the physiology of ketone bodies during and after exercise and in response to training, with specific interest in exploring the physiological basis for exogenous ketone supplementation and potential benefits for performance and recovery in athletes.

"An alternative fuel source to CHO and fat are ketone bodies

(KBs), namely acetoacetate (AcAc), acetone, and β-hydroxybutyrate (βHB), which are produced

in the liver during physiological states and nutritional manipulations that result in reduced CHO

There is increasing evidence that calorie restriction without malnutrition can extend longevity and delay the onset of age-associated disorders. Identifying the biochemical perturbations associated with different dietary habits would provide valuable insights into associations between metabolism and longevity. To reveal the effects of long-term dietary interventions on metabolic perturbations, we investigated serum and urinary metabolic changes induced by interactive high/low fat diet in combination with/without reduced caloric intake over a life span in mice using NMR-based metabonomics. We found that the high calorie dietary regime disturbed lipid metabolism, suppressed glycolysis and TCA cycles, stimulated oxidative stress, promoted nucleotide metabolism and gluconeogenesis, and perturbed gut microbiota-host interactions. Such changes could be modified by long-term low calorie intake. Most importantly, we found that the calorie intake index exerts a dominant effect on metabolic perturbations irrespective of dietary regime. Our investigation provides a holistic view of the metabolic impact of long-term dietary interventions, which are important for detecting physiological changes and dietary effects on mammalian metabolism.

In most modern societies, the relationship that many individuals have with food has fundamentally changed from previous generations. People have shifted away from viewing food as primarily sustenance, and rather now seek out foods based on pure palatability or specific nutrition. However, it is far from clear what optimal nutrition is for the general population or specific individuals. We previously described the Food Triangle as a way to organize food based on an increasing energy density paradigm, and now expand on this model to predict the impact of oxidative priority and both nutrient and fiber density in relation to caloric load. When combined with meal frequency, integrated energy expenditure, macronutrient oxidative priority, and fuel partitioning expressed by the respiratory quotient, our model also offers a novel explanation for chronic overnutrition and the cause of excess body fat accumulation. Herein, we not only review how metabolism is a dynamic process subject to many regulators that mediate the fate of ingested calories but also discuss how the Food Triangle predicts the oxidative priority of ingested foods and provides a conceptual paradigm for healthy eating supported by health and longevity research.

Cancer is the second leading cause of death worldwide and the morbidity is growing in developed countries. According to WHO, >14 million people per year are diagnosed with cancer and about 8 million die. Anti-cancer strategy includes chemo-, immune- and radiotherapy or their combination. Unfortunately, these widely used strategies often have insufficient efficacy and significant toxic effects on healthy cells. Consequently, the improvement of treatment approaches is an important goal. One of promising schemes to enhance the effect of therapy is the restriction of calorie intake or some nutrients. The combination of caloric restriction or its chemical mimetics along with anti-cancer drugs may suppress growth of tumor cells and enhance death of cancer cells. That will allow the dose of therapeutic drugs to be decreased and their toxic effects to be reduced. Here the possibility of using this combinatory therapy as well as the molecular mechanisms underlying this approach will be discussed.

Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacologic approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs, and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this review, we illustrate how dietary and pharmacologic therapies differ in their effect on tumor growth, proliferation, and metabolism and discuss the available preclinical and clinical evidence in favor of or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics.

SIGNIFICANCE:

To our knowledge, this is the first review article that comprehensively analyzes the -preclinical and preliminary clinical experimental foundations of both dietary and pharmacologic metabolic interventions in cancer therapy. Among several promising therapies, we propose treatment personalization on the basis of tumor genetics, tumor metabolism, and patient systemic metabolism.

Cancer is the second leading cause of death worldwide and the morbidity is growing in developed countries. According to WHO, >14 million people per year are diagnosed with cancer and about 8 million die. Anti-cancer strategy includes chemo-, immune- and radiotherapy or their combination. Unfortunately, these widely used strategies often have insufficient efficacy and significant toxic effects on healthy cells. Consequently, the improvement of treatment approaches is an important goal. One of promising schemes to enhance the effect of therapy is the restriction of calorie intake or some nutrients. The combination of caloric restriction or its chemical mimetics along with anti-cancer drugs may suppress growth of tumor cells and enhance death of cancer cells. That will allow the dose of therapeutic drugs to be decreased and their toxic effects to be reduced. Here the possibility of using this combinatory therapy as well as the molecular mechanisms underlying this approach will be discussed.

Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacologic approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs, and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this review, we illustrate how dietary and pharmacologic therapies differ in their effect on tumor growth, proliferation, and metabolism and discuss the available preclinical and clinical evidence in favor of or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics.

SIGNIFICANCE:

To our knowledge, this is the first review article that comprehensively analyzes the -preclinical and preliminary clinical experimental foundations of both dietary and pharmacologic metabolic interventions in cancer therapy. Among several promising therapies, we propose treatment personalization on the basis of tumor genetics, tumor metabolism, and patient systemic metabolism.

Biological clocks are autonomous anticipatory oscillators that play a critical role in the organization and information processing from genome to whole organisms. Transformative advances into the clock system have opened insight into fundamental mechanisms through which clocks program energy transfer from sunlight into organic matter and potential energy, in addition to cell development and genotoxic stress response. The identification of clocks in nearly every single cell of the body raises questions as to how this gives rise to rhythmic physiology in multicellular organisms and how environmental signals entrain clocks to geophysical time. Here, we consider advances in understanding how regulatory networks emergent in clocks give rise to cell type–specific functions within tissues to affect homeostasis.

"alignment of feeding and activity through restriction of food access to the nighttime in rodents protects from fatty liver (64), and similar strategies to control eating time may likewise improve human metabolic health (65)."

A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.

"We attribute this exceptional pattern to the peculiar life-history of this species, which skips reproduction in years with low food availability."

Telomeres are elongated in older individuals in a hibernating rodent, the edible dormouse (Glis glis).

Telomere shortening is thought to be an important biomarker for life history traits such as lifespan and aging, and can be indicative of genome integrity, survival probability and the risk of cancer development. In humans and other animals, telomeres almost always shorten with age, with more rapid telomere attrition in short-lived species. Here, we show that in the edible dormouse (Glis glis) telomere length significantly increases from an age of 6 to an age of 9 years. While this finding could be due to higher survival of individuals with longer telomeres, we also found, using longitudinal measurements, a positive effect of age on the rate of telomere elongation within older individuals. To our knowledge, no previous study has reported such an effect of age on telomere lengthening. We attribute this exceptional pattern to the peculiar life-history of this species, which skips reproduction in years with low food availability. Further, we show that this "sit tight" strategy in the timing of reproduction is associated with an increasing likelihood for an individual to reproduce as it ages. As reproduction could facilitate telomere attrition, this life-history strategy may have led to the evolution of increased somatic maintenance and telomere elongation with increasing age.

We studied the impact of hibernation and food supply on relative telomere length (RTL), an indicator for aging and somatic maintenance, in free-living edible dormice. Small hibernators such as dormice have ∼50% higher maximum longevity than non-hibernators. Increased longevity could theoretically be due to prolonged torpor directly slowing cellular damage and RTL shortening. However, although mitosis is arrested in mammals at low body temperatures, recent evidence points to accelerated RTL shortening during periodic re-warming (arousal) from torpor. Therefore, we hypothesized that these arousals during hibernation should have a negative effect on RTL. Here, we show that RTL was shortened in all animals over the course of ∼1 year, during which dormice hibernated for 7.5-11.4 months. The rate of periodic arousals, rather than the time spent euthermic during the hibernation season, was the best predictor of RTL shortening. This finding points to negative effects on RTL of the transition from low torpor to high euthermic body temperature and metabolic rate during arousals, possibly because of increased oxidative stress. The animals were, however, able to elongate their telomeres during the active season, when food availability was increased by supplemental feeding in a year of low natural food abundance. We conclude that in addition to their energetic costs, periodic arousals also lead to accelerated cellular damage in terms of RTL shortening. Although dormice are able to counteract and even over-compensate for the negative effects of hibernation, restoration of RTL appears to be energetically costly.

Studies have demonstrated that caloric restriction (CR) increases longevity in animals and also decreases the risk of diabetes, cardiovascular disease and cancer in humans without obesity.1 ,2 It is hypothesised that these favourable CR effects may be related to a reduction in metabolism, reduced core temperature and lowered triiodothyronine(T3).3 While it is unlikely that studies will ascertain whether CR extends life, intermediate length studies may be able to determine the safety, tolerability and feasibility of CR and its effects on chronic disease development and biomarkers correlated with longevity.2 This study aimed to examine the sustained effects of a 25% CR on health-related quality of life (QOL) in individuals without …

[Full text of this article]

[The below paper is pdf-availed.]

The effect of alternate-day caloric restriction on the metabolic consequences of eight days' bed rest in healthy lean men: a randomized trial.

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment, by overlapping mechanisms.

OBJECTIVE:

To test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after eight consecutive days in bed.

DESIGN:

Healthy, lean men (n = 20) were randomized to 1) 8 days' bed rest with 3 daily iso-energetic meals (control group, n = 10); and 2) 8 days' bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, DXA scans, magnetic resonance imaging of the abdomen and brain, VO2 max, and tests for cognitive function were performed before and after bed rest. In addition, daily fasting blood samples and 24 h glucose profiles by continuous glucose monitoring system were assessed during the 8 days bed rest period.

RESULTS:

Bed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared to the control group, ADCR was associated with improved and steadier glycemic control on fasting days, and higher glycemic fluctuation and indices of insulin resistance on overeating days.

CONCLUSIONS:

In contrast to our hypothesis, the metabolic impairment induced by eight days of bed rest was not counteracted by ADCR with overall energy balance.

Previous studies have demonstrated that autophagy induced by caloric restriction (CR) is neuroprotective against cerebral ischemia. However, it has not been determined whether intermittent fasting (IF), a variation of CR, can exert autophagy-related neuroprotection against cerebral ischemia. Therefore, the neuroprotective effect of IF was evaluated over the course of two weeks in a rat model of focal cerebral ischemia, which was induced by middle cerebral artery occlusion and reperfusion (MCAO/R). Specifically, the role of autophagy modulation as a potential underlying mechanism for this phenomenon was investigated. It was demonstrated that IF reduced infarct volume and brain edema, improved neurobehavioral deficits, and rescued neuronal loss after MCAO/R. Furthermore, neuronal apoptosis was decreased by IF in the rat cortex. An increase in the number of autophagosomes (APs) was demonstrated in the cortices of IF-treated rats, using immunofluorescence staining and transmission electron microscopy. Using immunoblots, an IF-induced increase was detected in microtubule-associated protein 1 light chain 3 (LC3)-II, Rab7, and cathepsin D protein levels, which corroborated previous morphological studies. Notably, IF reduced the accumulation of APs and p62, demonstrating that IF attenuated the MCAO/R-induced disturbance of autophagic flux in neurons. The findings of the present study suggest that IF-induced neuroprotection in focal cerebral ischemia is due, at least in part, to the minimization of autophagic flux disturbance and inhibition of apoptosis.

Methionine restriction (MR) is proven to increase the lifespan; and it also affects the bone density and the innate immune system. The aim of this study is to explore the effect of methionine restriction on bone density and natural killer (NK) cells. C57BL/6J mice were subjected to either basal diet (BD, containing 0.80% methionine) or methionine-restricted diet (containing 0.14% methionine). Mice with MR diet displayed reduced bone mass and decrease in the cytotoxicity of NK from the spleen, compared to BD animals. Also, mice with MR diet had an inferior body weight (P < 0.05) and higher plasma levels of adiponectin and FGF21 (P < 0.05) but lower concentrations of leptin and IGF-1 (P < 0.05). Overall, the investigation shows that methionine affects bone density and NK cell cytotoxicity.

Milk and dairy products: good or bad for human health? An assessment of the totality of scientific evidence.

The most recent evidence suggested that intake of milk and dairy products was associated with reduced risk of childhood obesity. In adults, intake of dairy products was shown to improve body composition and facilitate weight loss during energy restriction. In addition, intake of milk and dairy products was associated with a neutral or reduced risk of type 2 diabetes and a reduced risk of cardiovascular disease, particularly stroke. Furthermore, the evidence suggested a beneficial effect of milk and dairy intake on bone mineral density but no association with risk of bone fracture. Among cancers, milk and dairy intake was inversely associated with colorectal cancer, bladder cancer, gastric cancer, and breast cancer, and not associated with risk of pancreatic cancer, ovarian cancer, or lung cancer, while the evidence for prostate cancer risk was inconsistent. Finally, consumption of milk and dairy products was not associated with all-cause mortality. Calcium-fortified plant-based drinks have been included as an alternative to dairy products in the nutrition recommendations in several countries. However, nutritionally, cow's milk and plant-based drinks are completely different foods, and an evidence-based conclusion on the health value of the plant-based drinks requires more studies in humans.

CONCLUSION:

The totality of available scientific evidence supports that intake of milk and dairy products contribute to meet nutrient recommendations, and may protect against the most prevalent chronic diseases, whereas very few adverse effects have been reported.

Competing interests and funding: Tanja Kongerslev Thorning has no conflicts of interest to declare. Anne Raben is recipient of research funding from the Dairy Research Institute, Rosemont, IL, USA and the Danish Agriculture & Food Council.Tine Tholstrup is recipient of research grants from the Danish Dairy Research Foundation and the Dairy Research Institute, Rosemont, IL. The sponsors had no role in design and conduct of the studies, data collection and analysis, interpretation of the data, decision to publish, or preparation of the manuscripts. Sabita S. Soedamah-Muthu received funding from the Global Dairy Platform, Dairy Research Institute and Dairy Australia for meta-analyses on cheese and blood lipids and on dairy and mortality. The sponsors had no role in design and conduct of the meta-analyses, data collection and analysis, interpretation of the data, decision to publish, or preparation of the manuscripts. Ian Givens is recipient of research grants from UK Biotechnology and Biological Sciences Research Council (BBSRC), UK Medical Research Council (MRC), Arla Foods UK, AAK-UK (both in kind), The Barham Benevolent Foundation, Volac UK, DSM Switzerland and Global Dairy Platform. He is a consultant for The Bio-competence Centre of Healthy Dairy Products, Tartu, Estonia, and in the recent past for The Dairy Council (London). Arne Astrup is recipient of research grants from Arla Foods, DK; Danish Dairy Research Foundation; Global Dairy Platform; Danish Agriculture & Food Council; GEIE European Milk Forum, France. He is member of advisory boards for Dutch Beer Knowledge Institute, NL; IKEA, SV; Lucozade Ribena Suntory Ltd, UK; McCain Foods Limited, USA; McDonald’s, USA; Weight Watchers, USA. He is a consultant for Nestlé Research Center, Switzerland; Nongfu Spring Water, China. Astrup receives honoraria as Associate Editor of American Journal of Clinical Nutrition, and for membership of the Editorial Boards of Annals of Nutrition and Metabolism and Annual Review of Nutrition. He is recipient of travel expenses and/or modest honoraria (<$2,000) for lectures given at meetings supported by corporate sponsors. He received financial support from dairy organisations for attendance at the Eurofed Lipids Congress (2014) in France and the meeting of The Federation of European Nutrition Societies (2015) in Germany.

Relationship between FGF21 and UCP1 levels under time-restricted feeding and high-fat diet.

Fibroblast growth factor 21 (FGF21) exhibits a circadian oscillation, and its induction is critical during fasting. When secreted by liver and skeletal muscle, FGF21 enhances thermogenic activity in brown adipose tissue (BAT) by utilizing uncoupling protein 1 (UCP1) to dissipate energy as heat. Recently, it has been reported that UCP1 is not required for FGF21-mediated reduction in body weight or improvements in glucose homeostasis. As the relationship between FGF21 and UCP1 induction in tissues other than BAT is less clear, we tested the effect of restricted feeding (RF) and high dietary fat on FGF21 circadian expression and its correlation with UCP1 expression in liver and white adipose tissue (WAT). High dietary fat disrupted Fgf21 mRNA circadian oscillation but increased its levels in WAT. RF led to increased liver FGF21 protein levels, whereas those of UCP1 decreased. In contrast, WAT FGF21 protein levels increased under high-fat diet, whereas those of UCP1 decreased under RF. In summary, FGF21 exhibits circadian oscillation, which is disrupted with increased dietary fat. The relationship between FGF21 and UCP1 levels depends on the tissue and the cellular energy status.

"... The researchers' new model suggests that while high-carbohydrate diets were the most likely to support positive interactions in the microbiome, such benefits were relative to the protein intake of the host animal. ... There are many ways to achieve a good diet, and the same diet won't work in the same way in each person"

•Diet impact on host-microbiome interaction can be simplified for modeling

Summary

Diet influences health and patterns of disease in populations. How different diets do this and why outcomes of diets vary between individuals are complex and involve interaction with the gut microbiome. A major challenge for predicting health outcomes of the host-microbiome dynamic is reconciling the effects of different aspects of diet (food composition or intake rate) on the system. Here we show that microbial community assembly is fundamentally shaped by a dichotomy in bacterial strategies to access nitrogen in the gut environment. Consequently, the pattern of dietary protein intake constrains the host-microbiome dynamic in ways that are common to a very broad range of diet manipulation strategies. These insights offer a mechanism for the impact of high protein intake on metabolic health and form the basis for a general theory of the impact of different diet strategies on host-microbiome outcomes.

74 582 women from the Nurses' Health Study and 39 284 men from the Health Professionals Follow-up Study who were free from cardiovascular disease and cancer at baseline.

MAIN OUTCOME MEASURES:

Exposures included body mass index (BMI), score on the alternate healthy eating index, level of physical activity, smoking habits, and alcohol drinking while outcome was mortality (all cause, cardiovascular, cancer). Cox proportional hazard models were used to calculate the adjusted hazard ratios of all cause, cancer, and cardiovascular mortality with their 95% confidence intervals across categories of BMI, with 22.5-24.9 as the reference.

RESULTS:

During up to 32 years of follow-up, there were 30 013 deaths (including 10 808 from cancer and 7189 from cardiovascular disease). In each of the four categories of BMI studied (18.5-22.4, 22.5-24.9, 25-29.9, ≥30), people with one or more healthy lifestyle factors had a significantly lower risk of total, cardiovascular, and cancer mortality than individuals with no low risk lifestyle factors. A combination of at least three low risk lifestyle factors and BMI between 18.5-22.4 was associated with the lowest risk of all cause (hazard ratio 0.39, 95% confidence interval 0.35 to 0.43), cancer (0.40, 0.34 to 0.47), and cardiovascular (0.37, 0.29 to 0.46) mortality, compared with those with BMI between 22.5-24.9 and none of the four low risk lifestyle factors.

CONCLUSION:

Although people with a higher BMI can have lower risk of premature mortality if they also have at least one low risk lifestyle factor, the lowest risk of premature mortality is in people in the 18.5-22.4 BMI range with high score on the alternate healthy eating index, high level of physical activity, moderate alcohol drinking, and who do not smoke. It is important to consider diet and lifestyle factors in the evaluation of the association between BMI and mortality.

The db/db mouse is an animal model of diabetes in which leptin receptor activity is deficient resulting accelerated cardiomyopathy when exposed to angiotensin (AT). Toll-like receptors 4 and 2 (TLR4, TLR2) are pattern recognition receptors, that recognize pathogen-associated molecular patterns and exacerbate and release inflammatory cytokines. Fetuin A (Fet A) is a fatty acid carrier which affects inflammation and insulin resistance in obese humans and animals through TLRs. The aim of this study was to investigate the effect of caloric restriction (CR) on free fatty acids (FFA) level and the inflammatory response in diabetic cardiomyopathy.

METHODS AND RESULTS:

Left ventricular hypertrophy, increased fibrosis and leukocytes infiltration were observed in db/db AT treated hearts. Serum glucose, FFA, and cholesterol levels were elevated in db/db AT treated mice. Cardiac expression of PPARα increased while AKT phosphorylation was decreased.

CONCLUSIONS:

Cumulatively, CR elevated cardiac PPAR α improved the utilization of fatty acids, and reduced myocardial inflammation as seen by reduced levels of Fet A. Thus CR negated cardiomyopathy associated with AT in an animal model of diabetes suggesting that CR is an effective therapeutic approach in the treatment of diabetes and associated cardiomyopathy.

All organisms need to be capable of adapting to changes in the availability and composition of nutrients. Over 75 years ago, researchers discovered that a calorie restricted (CR) diet could significantly extend the lifespan of rats, and since then a CR diet has been shown to increase lifespan and healthspan in model organisms ranging from yeast to non-human primates. In this review, we discuss the effects of a CR diet on metabolism and healthspan, and highlight emerging evidence that suggests that dietary composition - the precise macronutrients that compose the diet - may be just as important as caloric content. In particular, we discuss recent evidence that suggests protein quality may influence metabolic health. Finally, we discuss key metabolic pathways which may influence the response to CR diets and altered macronutrient composition. Understanding the molecular mechanisms responsible for the effects of CR and dietary composition on health and longevity may allow the design of novel therapeutic approaches to age-related diseases.

Aging constitutes the central risk factor for major diseases including many forms of cancer, neurodegeneration, and cardiovascular diseases. The aging process is characterized by both global and tissue-specific changes in gene expression across taxonomically diverse species. While aging has historically been thought to entail cell-autonomous, even stochastic changes, recent evidence suggests that modulation of this process can be hierarchal, wherein manipulations of nutrient-sensing neurons (e.g., in the hypothalamus) produce peripheral effects that may modulate the aging process itself. The most robust intervention extending lifespan, plausibly impinging on the aging process, involves different modalities of dietary restriction (DR). Lifespan extension by DR is associated with broad protection against diseases (natural and engineered). Here we review potential epigenetic processes that may link lifespan to age-related diseases, particularly in the context of DR and (other) ketogenic diets, focusing on brain and hypothalamic mechanisms.

Age-dependent collapse of lipid homeostasis results in spillover of lipids and excessive fat deposition in non-adipose tissues. Ectopic fat contributes to lipotoxicity and has been implicated in the development of a metabolic syndrome that increases risk of age-associated diseases. However, the molecular mechanisms coupling ectopic fat accumulation with ageing remain obscure. Here, we use nonlinear imaging modalities to visualize and quantify age-dependent ectopic lipid accumulation in Caenorhabditis elegans. We find that ageing is accompanied by pronounced deposition of lipids in non-adipose tissues, including the nervous system. Importantly, interventions that promote longevity such as low insulin signalling, germline loss and dietary restriction, which effectively delays ageing in evolutionary divergent organisms, diminish the rate of ectopic fat accumulation and the size of lipid droplets. Suppression of lipotoxic accumulation of fat in heterologous tissues is dependent on HLH-30/TFEB and autophagy. Our findings in their totality highlight the pivotal role of HLH-30/TFEB and autophagic processes in the maintenance of lipid homeostasis during ageing, in addition to establishing nonlinear imaging as a powerful tool for monitoring ectopic lipid droplet deposition in vivo.

BACKGROUND: It is widely accepted that increasing adiposity is associated with insulin resistance and increased risk of type II diabetes. The predominant paradigm used to explain this link is the portal/visceral hypothesis. This hypothesis proposes that increased adiposity, particularly in the visceral depots, leads to increased free-fatty acid flux and inhibition of insulin-action via Randle's effect in insulin-sensitive tissues.

OBJECTIVES: In this review, limitations of this paradigm will be discussed and two other paradigms that may explain established links between adiposity and insulin resistance/diabetes will be presented.

CONCLUSIONS: The novel paradigms of ectopic fat and fat cell as an endocrine organ probably will constitute a new framework for the study of the links between our obesigenic environment and the risk of developing diabetes.

(a) Ectopic fat storage syndrome. Three lines of evidence support this concept. Firstly, failure to develop adequate adipose tissue mass (also known as 'lipodystrophy') results in severe insulin resistance and diabetes. This is thought to be the result of ectopic storage of lipid into liver, skeletal muscle and the pancreatic insulin-secreting beta cell. Secondly, most obese patients also shunt lipid into the skeletal muscle, the liver and probably the beta cell. The importance of this finding is exemplified by several studies demonstrating that the degree of lipid infiltration into skeletal muscle and liver highly correlates with insulin resistance. Thirdly, increased fat cell size is highly associated with insulin resistance and the development of diabetes. Increased fat cell size may represent the failure of the adipose tissue mass to expand and therefore to accommodate an increased energy influx. Taken together, these observations support the 'acquired lipodystrophy' hypothesis as a link between adiposity and insulin resistance. Ectopic fat deposition is therefore the result of additive or synergistic effects including increased dietary intake, decreased fat oxidation and impaired adipogenesis.

(b) Endocrine paradigm. This concept was developed in parallel with the 'ectopic fat storage syndrome' hypothesis. Adipose tissue secretes a variety of endocrine hormones such as leptin, interleukin-6, angiotensin II, adiponectin and resistin. From this viewpoint, adipose tissue plays a critical role as an endocrine gland, secreting numerous factors with potent effects on the metabolism of distant tissues.

The aim of the study was to investigate whether a very-low-energy diet (VLED) is a feasible and acceptable treatment option for type 2 diabetes in children and adolescents, and whether adherence can lead to rapid weight loss, reversal of type 2 diabetes and reduced liver fat as seen in adult studies.

METHODS:

Eight participants with type 2 diabetes and obesity, aged 7-16 years, non-medicated (n = 1) or treated with metformin (n = 7) and in some cases insulin (n = 3), followed a VLED (<3360 kJ/day) for 8 weeks, then transitioned to a hypocaloric diet (∼6300 kJ/day) that they followed to 34 weeks. HbA1c, fasting glucose and 2 h post-glucose load plasma glucose (2hG) were determined from fasting blood and an OGTT. Liver fat concentration was quantified using proton magnetic resonance spectroscopy. Adherence was defined as ≥5% weight loss during the 8 week VLED.

A VLED appears to be a feasible treatment option for some youth with type 2 diabetes on metformin therapy. Youth who agree to participate and adhere to a VLED achieve rapid weight loss, dramatic reductions in liver fat and reversal of type 2 diabetes. This highlights the capacity of a VLED to be used as a first-line treatment option in newly diagnosed youth. A larger trial with a control group and longer follow-up will be required to encourage a change in standard treatment.

Whilst obesity is associated with a higher risk of cognitive impairment, the influence of weight loss on cognitive function in obese/overweight people is equivocal. We conducted a meta-analysis of randomized controlled trials (RCTs) and longitudinal studies evaluating the influence of voluntary weight loss on cognitive function in obese/overweight individuals. Articles were acquired from a systematic search of major databases from inception till 01/2016. A random effect meta-analysis of weight loss interventions (diet, physical activity, bariatric surgery) on different cognitive domains (memory, attention, executive functions, language and motor speed) was conducted. Twenty studies (13 longitudinal studies=551 participants; 7 RCTs=328 treated vs. 140 controls) were included. Weight loss was associated with a significant improvement in attention and memory in both longitudinal studies and RCTs, whereas executive function and language improved in longitudinal and RCT studies, respectively. In conclusion, intentional weight loss in obese/overweight people is associated with improvements in performance across various cognitive domains. Future adequately powered RCTs are required to confirm/refute these findings.

The melanocortin neuronal system, comprised of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by lack of reliable biomarkers for brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, ß-endorphin (ß-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40h) and refeeding (24h) and from 8 obese subjects before and after 6-weeks of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35% and AgRP increased to 153% of baseline. During refeeding AgRP declined as leptin increased; CSF ß-EP increased but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline; CSF POMC and ß-EP decreased; plasma AgRP increased. At baseline AgRP correlated negatively with insulin and HOMA-IR and positively with the Matsuda index. Thus following chronic calorie restriction POMC and ß-EP declined in CSF while acutely only ß-EP changed. Plasma AgRP, however, increased after both acute and chronic restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

In the present study, we examined the effect of a very low-calorie diet(VLCD)-based obesity program on human gut microbiome diversity and metabolism during weight loss and weight maintenance.

METHODS:

Obese subjects underwent 3 months of VLCD followed by 3 months of weight maintenance. A lean and an obese control group were included. The microbiome was characterized by performing high-throughput dual-indexed 16S rDNA amplicon sequencing.

RESULTS:

At baseline, a significant difference in the Firmicutes/Bacteroidetes ratio between the lean and obese individuals was observed (p = 0.047). The VLCD resulted in significant alterations in gut microbiome diversity from baseline to 3 months (p = 0.0053). Acinetobacter represented an indicator species for the observed effect (indicator value = 0.998, p = 0.006). Metabolic analyses revealed alterations of the bacterial riboflavin pathway from baseline to 3 months (pnom = 0.0078). These changes in diversity and bacterial metabolism induced by VLCD diminished during the weight maintenance phase, despite sustained reductions in body weight and sustained improvements of insulin sensitivity.

CONCLUSION:

The present data show that a VLCD is able to beneficially alter both gut microbiome diversity and metabolism in obese humans, but that these changes are not sustained during weight maintenance. This finding might suggest that the microbiome should be targeted during obesity programs.

Roux-en-Y gastric bypass versus calorie restriction: support for surgery per se as the direct contributor to altered responses of insulin and incretins to a mixed meal.

To study the immediate effects of Roux-en-Y gastric bypass (RYGB) on glucose homeostasis, insulin, and incretin responses to mixed-meal tests compared with the effects of calorie restriction (CR).

SETTING:

University-affiliated bariatric surgery clinic.

BACKGROUND:

RYGB induces remission of type 2 diabetes (T2D) long before significant weight loss occurs. The time course and underlying mechanisms of this remission remain enigmatic. A prevailing theory is that secretory patterns of incretin hormones are altered due to rearrangement of the gastrointestinal tract. To what extent reduced calorie intake contributes to the remission of T2D is unknown.

METHODS:

Nine normoglycemic patients and 10 T2D patients were subjected to mixed-meal tests (MMT) 4 weeks before surgery before initiation of a very low calorie diet regimen (MMT-4 w), 1 day before surgery on a very low calorie diet regimen (MMT-1 d), on the morning of the first day after surgery (MMT+1 d; first postsurgical meal), and 6 weeks after surgery (MMT+6 w). Insulin, glucose, active glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured.

RESULTS:

CR lowered insulin in T2D patients, whereas glucose, GIP, and GLP-1 were unaffected. RYGB immediately increased plasma insulin and GIP. The GLP-1 response was delayed compared with the GIP response. T2D patients exhibited lower insulin responses after RYGB compared with normoglycemic patients. GIP responses were similar in both groups at all occasions, whereas T2D patients displayed markedly elevated GLP-1 responses 6 weeks after RYGB. Glucose was unaffected by CR and RYGB in both groups. Insulin sensitivity was unaffected by CR but improved with RYGB.

CONCLUSION:

RYGB exerts powerful and immediate effects on insulin and incretin responses to food, independently of changes caused by CR.

Inclusion of almonds in an energy-restricted diet has been reported both to enhance or to have no effect on weight loss. Their effects specifically on visceral body fat stores during energy restriction have not been widely examined. In addition, almond consumption has been associated with reduced blood pressure (BP), but whether this is linked to or independent of changes in body composition has to our knowledge not been examined.

OBJECTIVE:

We evaluated the effects of consuming almonds as part of an energy-restricted diet on body composition, specifically visceral adipose tissue (VAT) and BP, compared to a nut-free energy-restricted diet.

Moderate almond consumption by compliant overweight and obese individuals during energy restriction results in greater proportional reductions of truncal and total body fat as well as diastolic BP and hence may help to reduce metabolic disease risk in obesity.

It is necessary to employ myeloablative irradiation or chemotherapy to deplete the HSC niche to optimize hematopoietic stem cell transplantation. In a recent issue of Science, Taya and colleagues provide evidence for an alternative to the toxic chemoirradiative procedure by showing that a valine-restricted diet is sufficient to empty the bone marrow niche.

Hematopoiesis provides the body with a continuous supply of blood cells (see the Perspective by Sommerkamp and Trumpp). Taya et al. report that amino acid content is important for hematopoietic stem cell (HSC) maintenance in vitro and in vivo. Dietary valine restriction seems to “empty” the mouse bone marrow niche. Ito et al. used single-cell approaches and cell transplantation to identify a subset of HSCs at the top of the HSC hierarchy. Self-renewal relied on the induction of mitophagy, a quality-control process linked to a cell's metabolic state. Both studies may be helpful in improving clinical bone marrow transplantation.

Science, this issue p. 1103, p. 1152; see also p. 1156

Abstract

A specialized bone marrow microenvironment (niche) regulates hematopoietic stem cell (HSC) self-renewal and commitment. For successful donor-HSC engraftment, the niche must be emptied via myeloablative irradiation or chemotherapy. However, myeloablation can cause severe complications and even mortality. Here we report that the essential amino acid valine is indispensable for the proliferation and maintenance of HSCs. Both mouse and human HSCs failed to proliferate when cultured in valine-depleted conditions. In mice fed a valine-restricted diet, HSC frequency fell dramatically within 1 week. Furthermore, dietary valine restriction emptied the mouse bone marrow niche and afforded donor-HSC engraftment without chemoirradiative myeloablation. These findings indicate a critical role for valine in HSC maintenance and suggest that dietary valine restriction may reduce iatrogenic complications in HSC transplantation.

Manipulating mitophagy and dietary valine may lead to stem cell therapies

Summary

Hematopoietic stem cells (HSCs) are at the helm of the hierarchically organized hematopoietic system that ensures the lifelong production of all blood cells. HSCs depend on metabolic cues to secure their protective quiescent status and to enable rapid activation and replenishment of the blood system in response to stressful situations such as infections, excessive bleeding, or chemotherapy-induced myeloablation (1–3). On pages 1156 and 1152 of this issue, Ito et al. (4) and Taya et al. (5), respectively, uncover important roles for the degradation of defective mitochondria (mitophagy) and the amino acid valine in HSC maintenance and function.

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Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance.

Purified hematopoietic stem cells reveal that mitophagy plays a key role in their expansion.

Abstract

A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division balance, however, are not yet defined. Here we demonstrate, by characterizing at the single cell level a purified and minimally heterogeneous Tie2+ HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality-control process in mitochondria, plays an essential role in self-renewing expansion of Tie2+ HSCs. Activation of PPAR-fatty acid oxidation promotes to expand Tie2+ HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2+ HSCs. Our data thus identify mitophagy as a key mechanisms of HSC expansion, and suggest potential methods of cell fate manipulation through metabolic pathways.

Influence of age-related learning and memory capacity of mice: different effects of a high and low caloric diet.

Recent studies indicate that consumption of the different calorie diet may be an important way to accelerate or slow the neurodegenerative disorder related to age. Long-term consumption of a high-calorie diet affects the brain and increase the risk of neurodegenerative disorders. And consumption of a low-calorie diet (caloric restriction, CR) could delay aging, and protect the central nervous system from neurodegenerative disorders. The underlying mechanisms have not yet been clearly defined.

METHOD:

Thirty 6-week-old C57/BL6 mice were randomly assigned to a NC group (fed standard diet, n = 10), a CR group (fed a low-calorie diet, n = 10) or a HC group (fed a high-calorie diet, n = 10) for 10 months. Body weight was measured monthly. Learning and memory capacity were determined by Morris water maze. Pathological changes of the hippocampus cells were detected with HE and Nissl staining. The expression of GFAP was determined by immunofluorescence and western blot. The expression of mTOR, S6K and LC3B in the hippocampus was determined by immunofluorescence.

RESULTS:

After feeding for 10 months, compared with mice in the NC group, mean body weight was significantly higher in the HC group and significantly lower in the CR group. The result of Morris water maze showed that compared with mice in the NC group, the learning and memory capacity was significantly increased in the CR group, and significantly decreased in the HC group. HE and Nissl staining of the hippocampus showed cells damaged obviously in the HC group. In the hippocampus, the expression of GFAP, mTOR and S6K was increased in the HC group, and decreased in the CR group. The expression of LC3B was decreased in the HC group, and increased in the CR group.

CONCLUSIONS:

Long-term consumption of a high-calorie diet could inhibit autophagy function, and facilitate neuronal loss in the hippocampus, which in turn aggravate age-related cognition impairment. And consumption of a low-calorie diet (caloric restriction, CR) could enhance the degree of autophagy, protect neurons effectively against aging and damage, and keep learning and memory capacity better.

The present study was aimed at investigating the effects of sleep deprivation and dietary irregularities during Ramadan intermittent fasting (RIF) on selective fitness profile parameters in young untrained male Muslim individuals.

METHODS:

77 untrained Muslim men were recruited in the study. They were divided into the experimental group (EG; n=37, age: 22.62±1.77 years) and the control group (CG; n=40, age: 23.00±1.48 years). EG was undergoing RIF while CG abstained. Aerobic fitness, anaerobic capacity or high-intensity efforts (HIEs), agility, flexibility, vertical jump height and handgrip strength were measured on 8 separate occasions-15 days before RIF, 7 days before RIF, 1st day of RIF, 7th day of RIF, 15th day of RIF, 21st day of RIF, last day of RIF and 15 days after RIF.

The present investigation revealed that RIF had adverse effects on aerobic fitness, HIEs, agility and flexibility of young untrained Muslims of Kolkata, India. VJT, waist-hip ratio and handgrip strength were not affected by RIF in the studied population. Mild but statistically insignificant reduction in body mass was also reflected after the mid-Ramadan week.

Endogenous circadian clocks orchestrate several metabolic and signaling pathways that are known to modulate lifespan, suggesting clocks as potential targets for manipulation of metabolism and lifespan. We report here that the core circadian clock genes, timeless (tim) and period (per), are required for the metabolic and lifespan responses to DR in Drosophila. Consistent with the involvement of a circadian mechanism, DR enhances the amplitude of cycling of most circadian clock genes, including tim, in peripheral tissues. Mass-spectrometry-based lipidomic analysis suggests a role of tim in cycling of specific medium chain triglycerides under DR. Furthermore, overexpression of tim in peripheral tissues improves its oscillatory amplitude and extends lifespan under ad libitum conditions. Importantly, effects of tim on lifespan appear to be mediated through enhanced fat turnover. These findings identify a critical role for specific clock genes in modulating the effects of nutrient manipulation on fat metabolism and aging.

Protein ingestion following resistance-type exercise stimulates muscle protein synthesis rates, and enhances the skeletal muscle adaptive response to prolonged resistance-type exercise training. As the adaptive response to a single bout of resistance exercise extends well beyond the first couple of hours of post-exercise recovery, recent studies have begun to investigate the impact of the timing and distribution of protein ingestion during more prolonged recovery periods. Recent work has shown that overnight muscle protein synthesis rates are restricted by the level of amino acid availability. Protein ingested prior to sleep is effectively digested and absorbed, and thereby stimulates muscle protein synthesis rates during overnight recovery. When applied during a prolonged period of resistance-type exercise training, protein supplementation prior to sleep can further augment gains in muscle mass and strength. Recent studies investigating the impact of pre-sleep protein ingestion suggest that at least 40 g of protein is required to display a robust increase in muscle protein synthesis rates throughout overnight sleep. Furthermore, prior exercise allows more of the pre-sleep protein-derived amino acids to be utilized for de novo muscle protein synthesis during sleep. In short, pre-sleep protein ingestion represents an effective dietary strategy to improve overnight muscle protein synthesis, thereby improving the skeletal muscle adaptive response to exercise training.

Ageing is driven by a loss of transcriptional and protein homeostasis and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.

Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) is a routine method for gene expression analysis, and reliable results depend on proper normalization by stable reference genes. Caloric restriction (CR) is a robust lifestyle intervention to slow aging and delay onset of age-associated diseases via inducing global changes in gene expression. Reliable normalization of RT-qPCR data becomes crucial in CR studies. In this study, the expression stability of 12 candidate reference genes were evaluated in inguinal white adipose tissue (iWAT), skeletal muscle (Sk.M) and liver of CR mice by using three algorithms, geNorm, NormFinder, and Bestkeeper. Our results showed β2m, Ppia and Hmbs as the most stable genes in iWAT, Sk.M and liver, respectively. Moreover, two reference genes were sufficient to normalize RT-qPCR data in each tissue and the suitable pair of reference genes was β2m-Hprt in iWAT, Ppia-Gusb in Sk.M and Hmbs-β2m in liver. By contrast, the least stable gene in iWAT or Sk.M was Gapdh, and in liver was Pgk1. Furthermore, the expression of Leptin and Ppar-γ were profiled in these tissues to validate the selected reference genes. Our data provided a basis for gene expression analysis in future CR studies.

Hypoenergetic diets and resistance training (RT) have been suggested to be important components of weight loss strategy programs; however, there is little evidence as to the chronic effects of different macronutrient compositions on strength performance and muscle mass with RT. The purpose of this study was to compare the effects of carbohydrate restrictive (CRD) and conventional (CONV) diets combined with RT on strength performance and muscle thicknesses in overweight and obese participants already involved in RT programs. Twenty-one volunteers engaged in an eight-week progressive RT program three times per week were assigned to a CRD (< 30 g carbohydrate; n = 12; 30.7 ± 3.9 km·m-2) or a CONV (30% energy deficit; 55%, 15% and 30% energy from carbohydrate, protein and fat, respectively; n=9; 27.7±2.5 km·m-2).

METHOD:

At baseline and week 8, the participants underwent body composition assessment by anthropometry, measurement of muscle thickness by ultrasound, and three strength tests using isotonic equipment. Both groups had similar reductions in body mass and fat mass as well as maintenance of fat-free mass. Muscle strength increased 14 ± 6% in the CRD group (p = 0.005) and 19 ± 9% in the CONV group (p = 0.028), with no significant differences between the groups. No significant differences were detected in muscle thicknesses within or between the groups. In conclusion, hypoenergetic diets combined with RT led to significant increases in muscle strength and were capable of maintaining muscle thicknesses in the upper and lower limbs of overweight and obese participants, regardless of the carbohydrate content of the diets.

KEYWORDS:

Overweight; body composition; exercise; obesity; ultrasonography

The Scientist » News & Opinion » Daily News

Controlled Splicing Extends Life Span in Roundworms

Increasing the expression of an RNA splicing factor mimics dietary restriction, prolonging life in nematodes.

In the nematode worm Caenorhabditis elegans, aging is associated with dysregulation of RNA splicing, according to a paper published on Monday (December 5) in Nature. And restoring splicing homeostasis in these animals—via dietary restriction or over-expression of a key splicing factor—can extend the roundworms’ lives.

“The take-home message of the paper is that control of splicing is one of the key linchpins that actually may explain the association between dietary restriction and longevity,” said molecular geneticist Lorna Harries of the University of Exeter in the U.K., who was not involved in the research. “What’s been known previously is that [splicing] is associated with age and longevity . . . but this is the first report where we’ve been able to actually infer any sort of causality.”

As an organism ages, its cells gradually lose the capacity to faithfully convert the information in the DNA into functioning proteins, said William Mair of the Harvard T.H. Chan School of Public Health, who led the new study. “We know a lot about how DNA damage can lead to aging phenotypes, we know a lot about how loss of proper protein folding and of protein homeostasis can lead to aging,” said Mair, “but there’s an intermediary step about which we know very little”—splicing.

Recent studies have suggested that splicing becomes dysregulated in aging mice and humans. But “no one had asked whether it was causally linked,” said Mair. The question was, could loss of splicing homeostasis actually initiate aging?

To find an answer, Mair’s team turned to C. elegans. These roundworms live for only about three weeks and, in that time, age rapidly: they lose reproductive capacity, undergo immunosenescence, “even their skin wrinkles,” Mair said.

Mair and his colleagues examined roundworms containing an in vivo splicing reporter, which displays either green or red fluorescence in a strict tissue-specific manner, depending on the particular exon spliced into the reporter’s messenger RNA. In young roundworms (a day or two old), the expected pattern of green and red fluorescence was clearly visible in their transparent bodies. By day five, however, the boundaries between red and green tissues had become less firm. This indicated that “they’re beginning to have a loss of fidelity of this splicing process,” said Mair.

Separating the population of glowing roundworms into two groups—those with well-maintained splicing fidelity (the youthful pattern of fluorescence) and those without—the team found that the latter group died younger.

And when the roundworms were put on a calorie-restricted diet—known to extend life span in a range of organisms from yeast to mammals—the animals “maintained a youthful splicing pattern for way longer than if they’d been eating as much as they wanted,” Mair said.

Caloric restriction is thought to cause “a sort of SOS response” in animals, said Keith Blackwell of the Harvard Medical School–affiliated Joslin Diabetes Center who was not involved in the study. If an animal’s caloric intake is reduced, he explained, “it turns on beneficial mechanisms to protect itself and that makes it live longer. . . . But this [paper] is telling you that if you restrict the diet of an animal it makes RNA splicing better. How does that work? It’s really phenomenally interesting.”

Why splicing homeostasis declines with age and why restricting caloric intake prevents this decline are “the million-dollar questions,” said Harries.

To make inroads toward a mechanistic understanding, Mair’s team investigated which splicing factors might be involved in caloric restriction–induced longevity.

The researchers reduced activities of key splicing factors individually in the roundworms until discovering one that appeared to be specifically required for the life span increase. Without this splicing factor (splicing factor 1), said Mair, “if you give to the worms less food they don’t live a day longer.”

The researchers went on to show that by increasing the level of expression of splicing factor 1 in the roundworms, they could maintain splicing homeostasis and, importantly, increase these animals’ life spans without restricting their diets.

Because aging is a risk factor for many different diseases, an ultimate goal of Mair’s research is to try to therapeutically mimic the beneficial effects of dietary restriction without its downsides, he said. Indeed, “The open question is: Can we modulate RNA splicing to promote healthy aging in mammals? As yet,” he added, “we don’t know.”

Ageing is driven by a loss of transcriptional and protein homeostasis and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.

Despite well-documented evidence for lifespan extension by methionine restriction (MR), underlying mechanisms remain unknown. As methionine can alter S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the substrate and product of DNA methyltransferase-1 (DNMT1), we hypothesized that MR diet alters DNA methylation. Young (8-week-old) and adult (1-year-old) male C57BL/6J mice were fed diets with different levels of methionine (0.12%-MR, 0.84%-CD) for 12weeks. Functional indicators of DNA methylation, including global methylation (GM), gene-specific methylation (GSM) and LINE-1 methylation; and biochemical factors affecting DNA methylation, SAH, SAM, and DNMT1 were assessed in different tissues. MR altered DNA methylation depending on the age of intervention. While MR had no effect on hepatic GM in young animals, it increased GM by 27% over CD in adults (p<0.01). In comparison with young animals, hepatic GM levels were 17% lower in CD adults (p<0.05), but not different in MR adults. The MR-induced increase in hepatic GM was associated with a 38% decrease in SAH levels in adults (p<0.001), with SAH and GM levels being negatively correlated (r2=0.33, p<0.001). No changes were observed in DNMT protein levels in liver. In adipose tissue, MR caused a 6% decline in GM in adults (p<0.05), a corresponding 2-fold increase in SAH (p<0.05), and a 2-fold decrease in DNMT1 (p<0.01). MR caused both increases and decreases in GSM of liver and adipose. No changes were observed in LINE-1. Together, these findings provide evidence for protective effects of MR diet on hepatic DNA hypomethylation in adults, apparently mediated by SAH. These findings also indicate that altered DNA methylation might be playing a role in benefits conferred by MR diet.

Obesity and metabolic syndrome lead to the development of metabolic heart disease (MHD) that is characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and increased mitochondrial ROS. Caloric restriction (CR) is a nutritional intervention that protects against obesity, diabetes, and cardiovascular disease. Healthy adipose tissue is cardioprotective via releasing adipokines such as adiponectin. We tested the hypothesis that CR can ameliorate MHD and it is associated with improved adipose tissue function as reflected by increased circulating levels of high molecular weight (HMW) adiponectin and AMP-activated protein kinase (AMPK) in db/db mice.

METHODS:

Genetically obese db/db and lean db/+ male mice were fed either ad libitum or subjected to 30% CR for 5 weeks. At the end of the study period, echocardiography was carried out to assess diastolic function. Blood, heart, and epididymal fat pads were harvested for mitochondrial study, ELISA, and Western blot analyses.

RESULTS:

CR reversed the development of LVH, prevented diastolic dysfunction, and decreased cardiac mitochondrial H2O2 in db/db (vs. ad lib) mice. These beneficial effects on the heart were associated with increased circulating level of HMW adiponectin. Furthermore, CR increased AMPK and eNOS activation in white adipose tissue of db/db mice, but not in the heart.

CONCLUSIONS:

These findings indicate that even short-term CR protects the heart from MHD. Whether the beneficial effects of CR on the heart could be related to the improved adipose tissue function warrants future investigation.

KEYWORDS:

AMPK; adipose tissue; caloric restriction; metabolic heart disease

The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome.

Sterile inflammation is a cornerstone of immune activation in obesity and type 2 Diabetes Mellitus. The molecular underpinnings of this inflammation include nutrient excess-mediated activation of the innate immune NLRP3 inflammasome. At the same time, disruption of mitochondrial integrity is emerging as an integral control node in NLRP3 inflammasome activation and is also associated with caloric overload conditions including obesity and diabetes. Conversely, caloric restriction and fasting mimetic interventions alleviate these caloric excess-linked diseases and reduce inflammation and the NLRP3 inflammasome. The objective of this review is to integrate the findings linking mitochondrial integrity to the activation of the NLRP3 inflammasome and to evaluate how caloric restriction or caloric restriction mimetic compounds may play a role in attenuating the NLRP3 inflammasome and sterile inflammation.

1504 Background: Pancreatic cancer is the 4th leading cause of cancer death in both men and women in the U.S. Increased obesity has emerged as a risk factor for pancreatic cancer. Calorie restriction (CR), a dietary strategy that prevents or reverses obesity, has significant anti-cancer effects in a variety of tumor types and in both spontaneous and chemically-induced tumors. We have found in the K5.COX-2 transgenic mouse model of pancreatitis-driven pancreatic cancer that CR significantly protects from spontaneous pancreatic lesion formation as compared to the overweight and obese groups. Also, CR mice had significantly reduced serum IGF-1 levels and pro-inflammatory cytokine levels as compared to ad libitum fed (AL) and high fat (HF) fed mice. We hypothesized that decreased serum IGF-1 levels were responsible for the decreased tumor burden.

METHODS:

Orthotopic injections were performed on 6-8 week old Liver-specific IGF-1- Deficient (LID) and control mice (FVB/N and floxed IGF-1) with pancreatic tumor cells (JC101) derived from a transgenic K5.COX-2 animal. Tumors and pancreata were harvested and weighed 28 days after tumor injection.

RESULTS:

LID mice exhibited significantly reduced tumor burden (0.23±0.04) than either the floxed IGF-1 control (0.71±0.10) or FVB/N wild-type animals (0.71±0.04) following 28 days of growth. In addition to a reduction in serum IGF-1 in the LID mice, we also found a substantial decrease in serum levels of a panel of pro-inflammatory cytokines such as IFN-g, IL-1b, IL-4, IL-5, IL-10, IL-12, and TNF-a as compared to sera of control animals. Furthermore, we saw reduced proliferation and microvessel density in the tumor tissue of LID animals compared to controls by immunohistochemical staining.

CONCLUSIONS:

Using a model of pancreatitis-induced or orthotopically injected pancreatic tumorigenesis, our findings indicate that either transgenic manipulation or diet modulation of serum IGF-1 can alter the development of pancreatic cancer. Moreover, our findings suggest a strong link between expression of IGF-1 and pro-inflammatory cytokines in response to CR and the prevention of tumor growth. This could have direct implications for the prevention and control of pancreatic tumors due to chronic inflammation and/or obesity.

Total caloric restriction (CR) without malnutrition is a well-established experimental approach to extend life span in laboratory animals. Although CR in humans is capable of shifting several endocrinological parameters, it is not clear where the minimum inflection point of the U-shaped curve linking body mass index (BMI) with all-cause mortality lies. The exact trend of this curve, when used for planning preventive strategies for public health is of extreme importance. Normal BMI ranges from 18.5 to 24.9; many epidemiological studies show an inverse relationship between mortality and BMI inside the normal BMI range. Other studies show that the lowest mortality in the entire range of BMI is obtained in the overweight range (25-29.9). Reconciling the extension of life span in laboratory animals by experimental CR with the BMI-mortality curve of human epidemiology is not trivial. In fact, one interpretation is that the CR data are identifying a known: "excess fat is deleterious for health"; although a second interpretation may be that: "additional leanness from a normal body weight may add health and life span delaying the process of aging." This short review hope to start a discussion aimed at finding the widest consensus on which weight range should be considered the "healthiest" for our species, contributing in this way to the picture of what is the correct life style for a long and healthy life span.

Obesity-related cellular, metabolic, and molecular alterations have been shown to increase cancer risk and tumor progression and are associated with poorer therapeutic outcome in cancer patients. However, the impact of obesity and weight-control interventions on the therapeutic response in melanoma is poorly understood.

METHODS:

High fat diet (HFD)-induced obese mouse model was used in this study to evaluate the outcome of dacarbazine (DTIC) therapy in melanoma. We employed LC-MS/MS to determine the quantity of the drug in tumor, and in various tissues. Unique in vitro approach was used to complement in vivo findings by culturing melanoma cells in either conditioned medium (CM) obtained from differentiated adipocytes or in serum collected from experimental mice.

RESULTS:

We report that diet-induced obesity impairs the outcome of DTIC therapy and reduces overall survival in tumor-bearing mice. We provide evidence that obesity restricts the accessibility of DTIC to tumor tissue. Critically, upon curtailing adiposity, accumulation and efficacy of DTIC is significantly improved. Moreover, using appropriate in vitro approaches, we show that melanoma cells exhibit a drug-resistant phenotype when cultured in serum collected from diet-induced obese mice or in CM collected from 3T3-L1 adipocytes. The impaired therapeutic response to DTIC in obese state is mediated by fatty acid synthase (FASN), caveolin-1 (Cav-1), and P-glycoprotein (P-gp). The response to DTIC and overall survival were improved upon employing weight control interventions in the tumor-bearing HFD-fed (obese) mice.

CONCLUSIONS:

This study indicates that obesity not only supports rapid melanoma progression but also impairs the outcome of chemotherapy, which can be improved upon employing weight control interventions. From clinically relevant point of view, our study exemplifies the importance of lifestyle interventions in the treatment of obesity-promoted cancers.

In animals, dietary energy restriction is reported to increase longevity, whereas in humans, all cohort studies from Western countries have not shown an association between the low energy intake and longevity. We examined the association between total energy intake and longevity in Japan where dietary pattern is different from that in the West.

METHODS:

A total of 7,704 Japanese aged 30-69 years were followed from 1980 to 2009. Participants were divided into the quintiles of total energy (kcal/day) based on data collected from the National Nutrition Survey. Hazard ratios and 95% confidence intervals (CIs) were derived through the use of Cox proportional hazards models to compare the risk of death across and between the quintiles.

RESULTS:

There was a significant association between increased energy intake and all-cause mortality risk in only men (P for linear trend=0.008). In cause-specific analysis, compared with the lowest quintile, there was rise in coronary heart disease (CHD) mortality among men (HR; 2.63, 95%CI; 0.95-7.28, P for linear trend 0.016) and women (HR; 2.91, 95%CI; 1.02-8.29, P for linear trend 0.032) and cancer mortality among men (HR; 1.50, 95%CI; 0.999-2.24, P for linear trend 0.038) in the top quintile.

CONCLUSION:

We observed significant associations of high energy intake with all-cause and cancer mortality among men and with CHD mortality among men and women. Further studies are needed to confirm the benefits of caloric restriction.

Obesity is a deleterious condition characterized by excess adipose tissue deposition and a body mass index greater than 30.0. It is a major risk factor for many diseases, including coronary heart disease and non-insulin dependent diabetes mellitus. Obesity leads to systemic low-grade inflammation caused by cytokines and adipokines. Although obesity has effects on several bodily systems, the lymphatic system is especially important since its relationship with obesity is bidirectional. Obesity is the major contributing factor to the progression and development of lymphedema and impaired lymphatic function is thought to regulate the pathology of obesity in organ systems via modulation of the differentiation and migration of inflammatory cells. It has been shown obesity leads to lymphatic dysfunction which is characterized by impaired lymphatic vessel pumping and density, increased lymphatic vessel leakiness, and altered lymphatic endothelial cell gene expression (Savetsky et al. 2014). Despite the clinical importance of lymphatic physiology in obese patients, an effective therapeutic strategy to regulate lymphatic function remains to be determined.

A rapidly growing body of evidence has shown that chromatin undergoes radical alterations as an organism ages, but how these changes relate to aging itself is an open question. It is likely that these processes contribute to genomic instability and loss of transcriptional fidelity, which in turn drives deleterious age-related phenotypes. Interventions associated with increased healthspan and longevity such as reduced insulin / IGF signalling (IIS), inhibition of mTOR and energy depletion resulting in SIRT1 / AMPK activation, all have beneficial effects which ameliorate multiple facets of age-associated decline. The impact of these interventions on the epigenome is less certain. In this review we highlight the potential of these interventions to act directly upon the epigenome and promote a youthful chromatin landscape, maintaining genetic and transcriptional memory throughout the lifecourse. We propose that this is a fundamental mechanism through which these interventions are able to curtail the incidence of age-related disease. By revisiting these well characterised interventions, we may be able to identify targetable effectors of chromatin function and use this knowledge to enhance healthspan and longevity in human populations through the measured application of dietary and small molecule interventions.

Cholesterol has attracted significant attention as a possible lifespan regulator. It has been reported that serum cholesterol levels have an impact on mortality due to age-related disorders such as cardiovascular disease. Diet is also known to be an important lifespan regulator. Dietary restriction retards the onset of age-related diseases and extends lifespan in various organisms. Although cholesterol and dietary restriction are known to be lifespan regulators, it remains to be established whether cholesterol is involved in dietary restriction-induced longevity. Here, we show that cholesterol deprivation suppresses longevity induced by intermittent fasting, which is one of the dietary restriction regimens that effectively extend lifespan. We also found that cholesterol is required for the fasting-induced upregulation of transcriptional target genes such as the insulin/IGF-1 pathway effector DAF-16 and that cholesterol deprivation suppresses the long lifespan of the insulin/IGF-1 receptor daf-2 mutant. Remarkably, we found that cholesterol plays an important role in the fasting-induced nuclear accumulation of DAF-16. Moreover, knockdown of the cholesterol-binding protein NSBP-1, which has been shown to bind to DAF-16 in a cholesterol-dependent manner and to regulate DAF-16 activity, suppresses both fasting-induced longevity and DAF-16 nuclear accumulation. Furthermore, this suppression was not additive to the cholesterol deprivation-induced suppression, which suggests that NSBP-1 mediates, at least in part, the action of cholesterol to promote fasting-induced longevity and DAF-16 nuclear accumulation. These findings identify a novel role for cholesterol in the regulation of lifespan.

We all—more or less—think about aging, and our ancestors did too. In Greek mythology, the god of old age, Geras, was often depicted as a shriveled-up old man holding a cane, while the goddess of youth, Hebe, was the young woman keeper of the Fountain of Youth. When we think of aging, even though life expectancy has gone up, it is the increased risk for maladies such as cardiovascular disease, cancer, diabetes, sarcopenia, osteoporosis, and cognitive decline that is more worrisome than the end point.

Main Text

What makes us age, and can we promote healthy aging? For this Special Issue of Cell Metabolism on Aging, we feature primary research articles and a collection of Crosstalk, Review, Perspective, and Essay articles in aging biology. We hope that this selection will kick-start insightful discussions that we can continue at our upcoming Cell Symposium “Aging and Metabolism” in Spain (July 10–12). We are including a sneak preview of thoughts from the meeting speakers, as well as other leaders in the aging field, in our Voices article.

The animal kingdom is full of surprises when it comes to longevity. For example, the naked mole rat, the longest-lived rodent, can live up to 28 years, and the bowhead whale, at 200 years, has the longest lifespan of all animals. Clues into healthy aging may also come from elephants, which carry multiple copies of the tumor-suppressor gene TP53 in their genomes, offering an explanation for their very low cancer rate (Abegglen et al., 2015). Tissue metabolites across 26 mammalian species, representing ten taxonomical orders, were investigated in a Cell Metabolism study in order to identify metabolites correlating with species lifespan (Ma et al., 2015). On the other hand, the African turquoise killifish helps us understand the genetics of accelerating aging (Valenzano et al., 2015). In humans, while progeroid syndromes have taught us how specific gene mutations can dramatically shorten lifespan, the basis for exceptional longevity in centenarians has proven to be much more complex, involving numerous genetic variants, reflecting the interaction with environmental factors.

Historically, model organisms, including yeast, worms, and fruit flies, have been instrumental in identifying some of the key genes and signaling pathways regulating lifespan. The past decades have witnessed a rejuvenation of the aging field as new molecular targets underlying the biology of aging have emerged, such as sirtuins and mTOR. These fundamental genetic and epigenetic drivers are conserved across the animal kingdom from yeast to humans and have revealed how intricately intertwined metabolism and aging are. Barzilai and colleagues discuss the complexity of the somatotrophic axis in aging in their Review article, while Kennedy and Lamming provide an update on mTOR, a key hub linking metabolism and aging. Using C. elegans as a model in their research article, Kenyon and colleagues explore the link between starvation-induced quiescence, proteostasis, and aging (Roux et al., 2016). Steffen and Dillin pick up this topic further and discuss how changes in translation affect proteostasis and longevity, while Wiley and Campisi delve into the connections between metabolism and cellular senescence.

Given its multifactorial nature, aging may well be the most complex physiological question. How do genetics, diet, and other lifestyle factors interact to affect longevity? A critical element underlying this trifecta is the influence of sex on biology, as exemplified by the recent NIH mandate to “consider sex as a biological variable” that needs to “be factored into research designs, analyses, and reporting” (NIH notice NOT-OD-15-102, Consideration of Sex as a Biological Variable in NIH-funded Research). Throughout this Special Issue, several authors, such as deCabo and colleagues, who look at the effects of sex and genetics in response to calorie restriction, emphasize how fundamental this point is (Mitchell et al., 2016). In this vein, Fisher and Austad review sex differences in lifespan and conclude that, though more physically limited than men, women are the longer-lived sex. Could the physical limitations be, at least in part, due to skeletal muscle atrophy? Zierath and colleagues offer intriguing answers in their Review about healthy muscle aging. Karsenty and colleagues investigate bone-muscle communication and identify osteocalcin as a strength-promoting hormone that naturally declines with age (Mera et al., 2016). Using a novel mass spectrometry assay, LeBrasseur and colleagues show that the previously thought putative rejuvenating factor, GDF11, does not decrease during aging in humans and, if anything, has a negative health association in older adults with cardiovascular disease (Schafer et al., 2016). Could the “Fountain of Youth” be “just down the street at your nearest neighborhood gym” as posited by Zierath and colleagues? Not so fast, say Longo and Panda in their Perspective, as “everyday dietary choices can clearly accelerate aging” and “increase the incidence of age-related diseases.”

The growing number of insights into what makes us age has led some to investigate ways to slow the process down. Considerable pharmaceutical and biotech research efforts are currently being focused in this direction such as Kronos Longevity Research, Proteostasis Therapeutics, and Calico, to name a few, not only looking into novel therapeutics, but also revisiting old ones such as hormonal treatments and antioxidants. The immunosuppressant rapamycin, which is one of the first drugs shown to extend lifespan in a variety of species, including mammals, is currently being tested in a clinical trial for the treatment of Hutchinson-Gilford progeria syndrome. In their Essay, Barzilai and colleagues explain why they chose the anti-diabetic drug metformin for their Targeting Aging with Metformin (TAME) clinical trial of 65+ humans as a paradigm for the evaluation of pharmacological approaches to combat aging. Coming back to diet as a therapy, Elysium Health markets nutritional supplements (nutraceuticals) aimed at boosting NAD levels. Intriguing research in this issue by Chini and colleagues identifies CD38 as the enzyme responsible for the age-related decline in endogenous NAD levels and shows that CD38 can modulate the response to NAD replacement therapies in mice.

So it looks like there’s hope for Geras after all; he might soon be able to ditch his cane, spend less time worrying about his health, and post more selfies while skateboarding. Rock on!

The genetic mechanisms mediating longevity and maximum lifespan of the human species are likely different than those explaining differences in life expectancy and healthspan across individuals. Both of these perspectives are important and can be separated and explored using genomic data.

There is substantial natural variation in lifespan, from a few months in shrews to a couple centuries in bowhead whales. Some organisms, such as Hydra, seem not to age at all. I started out as an evolutionary biologist and was fascinated by the paradox of aging. How can a process of loss of function, fertility, and viability evolve by natural selection? Extrinsic hazards such as disease, predation, and accidents are important because they limit the survival of even a potentially immortal organism. Aging can then evolve, not because it is an advantage, but purely as a side effect of mutations that impair older adults. Aging is not like development, with well-oiled genetic machinery making sure that the right things happen in the right places at the right times. It is haphazard and varies between individuals—we do not all suffer from the same age-related conditions. It therefore came as a surprise to discover that not only can mutations in single genes ameliorate aging, but mechanisms of aging are evolutionarily conserved. Lowered activity of the insulin/IGFTOR nutrient-sensing signaling network, central to metabolic control, also ameliorates aging in worms, flies, mice, and probably humans. It can also combat pathology in animal models of human age-related diseases. The molecular mechanisms are tissue-specific and systemic, and targeting this network with drugs holds the prospect of broad-spectrum, preventative medicine for the diseases of human aging.

The Essence of Aging

Toren Finkel

Winston Churchill once observed that “out of intense complexities, intense simplicities emerge.” Perhaps nothing in the biological sciences seems as complex as aging. Because of this, for many years the study of aging seemed to me to be mostly a descriptive and correlative endeavor. Much has changed over the last two decades. Primarily as a result of the use of simple model organisms, well-defined, evolutionarily conserved pathways have been elucidated, yielding remarkable insight and providing much-needed excitement in the field. I guess what remains missing for me is the emergence of the simplicity. How do we now fit and interpret the wealth of data from many long-lived species into a single coherent framework? When does the generalized theory of aging finally emerge? While the long-held notion of the “free radical theory of aging” is what personally enticed me into the field, this conceptual framework no longer seems tenable. Now I suppose I would favor a general theory that suggests that caloric restriction or genetic interventions that extend lifespan do so by altering how energy is partitioned within an organism. Using a reduction of mTOR activity as an example, maybe long life means using less ATP for biosynthetic purposes (e.g., protein translation) and directing more energy for maintenance and repair (e.g., autophagy). Maybe the secret of staying young is being less dour and more dauer at the same time. Alas, it’s probably not that simple.

The “Aging” Future

Amita Sehgal

While getting old can be a daunting prospect, it is usually preferred over the alternative. Some of the fear comes from a lack of understanding of what happens with age and the inability to do anything about it. Given the continuing demographic shift to older ages in developed countries, we clearly need to address health problems of the elderly. Behavioral and physiological processes break down with age and can be modeled in animals ranging from worms and flies to primates. While mechanisms underlying aging remain a mystery and absolutely have to be addressed, there is agreement on an important contribution of metabolic factors. Our own work supports a link of metabolism with sleep cycles, as well as more generally with circadian rhythms, both of which deteriorate with age. We suggest that lifestyle interventions, which include regulation of daily cycles of sleep and feeding, are important considerations for dealing with aging and age-related disorders.

How Universal Is Aging?

Pankaj Kapahi

The commonly held view in the field is that organismal aging and age-related functional decline and pathology have common mechanistic origins. Thus interventions that slow aging will be able to not only extend lifespan but also slow the decline of various age-related diseases and functions, including cognitive and physical. However, if aging is instead due to distinct and parallel mechanisms acting in a tissue-specific manner, efforts to identify interventions that extend lifespan will fail to extend healthy years of life. Thus there is an urgent need to test these ideas, formally, as it is possible that, due to selection bias, mostly results with a positive correlation between health span and lifespan are reported. A critical step in this direction is to establish better models to study age-related decline in tissue-specific functions and understand their relationship to organismal aging. Furthermore, are individual sex- or species-specific differences likely to influence the impact of anti-aging interventions? Important clinical implications arise from understanding the questions above. Investigating tissue-specific aging mechanisms would allow the possibility of multiplex interventions to extend health span irrespective of changes in lifespan. Individual-specific aging mechanisms would lead to personalized dietary and pharmacological interventions tailored to individuals for optimal effects.

The Old Dormant Metabolism

Valter Longo

Organisms ranging from bacteria to emperor penguins and bears regularly enter alternative metabolic phases, activated in response to starvation conditions. Although fasting was historically also common for humans, it has largely disappeared from common practice, due to an overabundance of food but also to the influence of social context on eating behavior. Surprisingly, studies of starving stationary-phase bacteria and yeast or of hibernating and fasting mammals have been few compared to those of microorganisms or mammals exposed to excess nutrients. The reason for this preference is not clear, but it may be related to what Einstein described as “taking a board of wood, looking for its thinnest part, and drilling a great number of holes through it.” Thus, studies of starvation response phases in both simple organisms and mammals represent a challenge but also an excellent opportunity for young researchers entering the aging and metabolism field. Addressing questions like “how does a starved yeast spore survive many-fold longer than a yeast incubated in nutrient-rich media? ” or “can all mammals turn on a dormant switch to enter slow senescence hibernation states?” could provide insights not only into the biology of alternative phases but also into how different metabolic pathways can contribute to longevity and health span extension.

Unrestricted Perspective on Aging

Rozalyn Anderson

The ability of caloric restriction (CR) to delay aging was first recognized in rodent experiments conducted by Clive McCay in the 1930s. Although first viewed simply as a passive delay in onset and progression of aging processes, technological developments in the intervening years have revealed molecular insights into CR mechanisms. The current view is that CR is an active process where longevity factors impinging on the root causes of aging are directly recruited. Many of the candidate factors identified to date reside at the intersection of growth and metabolism; several also moonlight in cellular resilience and survival pathways. Gene expression studies have shown that the core signature of CR is a shift in energy metabolism, and metabolic analysis confirms CR-induced metabolic differences at the whole-body, tissue, and cellular level. Exactly how pathways of energy derivation and consumption link to aging is as yet unclear, but metabolic dysfunction is a shared feature of myriad age-related diseases. From the perspective of CR research we can begin to identify the critical events that occur in the course of normal aging to create enhanced disease vulnerability and increased morbidity. Given that the benefits of CR are conserved in nonhuman primates, it seems highly likely these insights will prove translatable to human aging.

Aging and Miracle Microbes

Tim Spector

Over the last 20 years I have studied most of the “omics” and their role in aging, and they have a gentle correlation with increasing age from 40 to 90. These include methylation, telomere length, gene expression, proteomics, metabolomics, and glycomics. But one omic appears to be different: our gut microbiome. Our 100 trillion gut microbes have 200 times more genes than we do, each capable of producing a huge range of proteins and metabolites that regulate our metabolism and immune systems. Combined data from the American/British gut projects and our UK twins show little age effects until after the age of 75, when there is a dramatic loss of microbe species. This strongly predicts frailty and co-morbidities. I am fascinated to see if this loss of beneficial anti-inflammatory species is the consequence of the worsening diet and nutrition in old people or the possible cause of the tipping point for the faltering biological systems in many elderly folk. Either way, we can learn how to improve nutrition in the elderly, and finding the beneficial microbes that are responsible for protecting us against old age problems opens the door, eventually, for novel therapies as well the immediate option of starting trials of probiotics to extend disease-free aging.

Study Stem Cell Metabolism!

Heinrich Jasper

Ever since the discovery that reducing insulin signaling activity extends lifespan in a variety of model systems, and ever since the observation that dietary restriction extends lifespan, it has become clear that the control of energy metabolism and the coordination of metabolic activity across tissues is central to the maintenance of a healthy adult. But how exactly is metabolic homeostasis maintained in the short term as well as over the course of a lifetime of decades? And what triggers the decline in metabolic homeostasis in the aging organism? We are only beginning to tackle these questions, and a concerted effort using genetic, biochemical, and “omics” approaches is required to find answers. Particularly fascinating is the impact of metabolic activity on stem cell function and regeneration. It is clear that diet and metabolism have profound impacts on somatic stem cell activity, and understanding the mechanism(s) linking these processes is critical. There are also indications that modulating metabolism in stem cells specifically allows regulating their self-renewal, maintenance, differentiation, and lineage commitment. Insight into age-related changes in stem cell metabolism and into the associated changes in stem cell function will thus likely uncover critical new avenues for intervention into aging and age-related diseases. We are in exciting times.

Is Epigenetic Decline a Cause of Aging?

David A. Sinclair

Chromatin is a complex structure whose organization is set down during embryogenesis so that is can compact, stabilize, and regulate our genomes for the next eight to ten decades. The structure undergoes thousands of chemical and structural alterations each minute in response to both internal and external signals, making chromatin arguably the most difficult structure to maintain. Youthful patterns of nuclear structure and gene expression are lost with the passing of time. Increasing evidence points to these changes being a key driver of aging and age-related diseases. Studies in budding yeast in the 1990s first showed that changes in chromatin structure, largely in response to chromosomal breaks, result in cumulative changes in gene expression that promote aging. Evidence increasingly indicates that a similar process occurs in mammals: changes in chromatin resulting from a DNA break may change gene expression such that a cell has a decreased ability to prevent additional breaks, setting up a positive feedback loop. Proving this in a living mammal remains a serious challenge but one worth taking, for unlike mutations, age-related epigenetic changes might be reversible.

Growth Hormone and Aging

Andrzej Bartke

Work led by Dr. Brown-Borg in our laboratory in the ’90s showed that mice with hereditary growth hormone (GH) deficiency live much longer than their normal siblings and exhibit characteristics of delayed and “healthy” aging. These findings prompted the change of focus of our research from endocrinology of reproduction to biology of aging. Entering this new field, I was struck by the excitement of many new and often unexpected findings and the efforts to use novel information to explain what was known about aging. We were encouraged by watching the (in retrospect, understandable) suspicions about our claims being slooowly replaced by confirmation and acceptance and by the work of many groups providing tantalizing evidence that much of what we have been finding in long-lived mice applies also to long-lived people. Now the complex phenotypes of long-lived GH-deficient and GH-resistant mice have been characterized in detail, and thus it is possible to ask questions about the underlying mechanisms. What we are most interested in is identifying alterations in glucose homeostasis and energy metabolism that lead to longer and healthier life, and in elucidating the role of hormonal signaling during development in programing the trajectory of aging. I think that the key challenges for the field are the surprisingly slow acceptance of the importance of slowing the aging process as a strategy of disease prevention and the difficulties in obtaining research funding.

CNS-Dependent Control of Integrated Physiology in Aging and Metabolism

Jens C. Brüning

The coordinated regulation of caloric intake, stress responses, and metabolic pathways represents a key determinant of lifespan and health span in a broad spectrum of model organisms. Recently, our understanding of neurocircuitries underlying the CNS control of energy intake and expenditure has largely expanded. The melanocortin circuitry comprising agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus represent key regulators of feeding behavior. They also coordinate systemic insulin sensitivity via control of autonomic innervation of metabolically relevant target tissues, such as liver and brown adipose tissue. Thus, these neurocircuits are key regulators of systems physiology by coordinately regulating calorie intake as well as nutrient partitioning according to energy availability. In addition, these neurons regulate innate immune responses and bone mineral density. The notion that their activity is not only regulated according to fluctuations in energy communicating hormonal signals, such as insulin and leptin, but also responds to the sensory perception of food defines them as primary effectors, adapting physiological processes in response to the internal mileu of the organism and the environment. Collectively, these integrative functions of need-response regulatory neurocircuits may define them as control centers of the aging process in addition to controlling the onset of aging-associated diseases.

Toward Productive Aging

Shin-ichiro Imai

Over the past 30 years, evolutionarily conserved signaling pathways and regulators for aging and longevity control have been identified, including insulin/IGF-1 signaling, mTOR signaling, and NAD+-dependent sirtuins. With this exciting development, we can now address the following questions: (1) In which organ does each signaling pathway or regulator play a major role in affecting the process of aging and determining lifespan? (2) What perturbations affect their functions in these specific organs? (3) How do those functional changes in such specific organs start affecting other organs and tissues? (4) Can we intervene in such a systemic process? In mammals, recent studies demonstrate that the hypothalamus functions as the “control center of aging,” throwing new light on the hypothalamic/neuroendocrine theory of aging proposed by Vladimir Dilman in 1971 and the idea of “the aging clock” proposed by Arthur Everitt in 1973. Both suspected that some feedback mechanism that involved the hypothalamus might run “the genetic program of development and aging” or “the aging clock.” Remarkably, it has been shown that adipose tissue modulates the function of the control center through the secretion of a key NAD+ biosynthetic enzyme, NAMPT, fueling more enthusiasm to intervene in the process of aging with NAD+ intermediates. This is the beginning of another exciting era of aging research, and new interventions are now on the horizon to achieve productive aging.

Interventions: Where Are We Now?

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Rafael de Cabo

Toward the end of my PhD in nutrition at Purdue, Rick Weindruch came to visit and gave a seminar about aging and caloric restriction. It was fascinating, and I was hooked into aging research! Soon after that, I searched for and found a postdoctoral position working at the National Institute on Aging in Baltimore with the intramural leaders in calorie restriction research. I started asking questions aimed to help understand the metabolic and signaling consequences of CR in our model organisms. Our team was developing the concept of caloric restriction mimetics, compounds that would have the effects of CR without the need to cut down on calories, a concept that at that time was revolutionary. Today, the field has successfully identified targets, screened libraries, and tested a dozen compounds that are the new non-genetic tools to extend health and lifespan in mice. But we still know little about their effects on delaying specific aspects of aging. So is now the time to start thinking about translating these findings into the clinic? Sure, but before that, we still need to define: how would we measure the success of the intervention? Do we have a good set of biomarkers to follow? Which are our target populations? Which disease(s) are we going to affect? When should these populations initiate treatment, and under what conditions will any of these interventions be safe and sound for an aging population? Only time and good science will tell.

The Path to “Intelligent” Diets

Manuel Serrano

The realization that changes in metabolism can delay the systemic deterioration associated with organismal aging is, in my opinion, one of the greatest recent advances in the field of aging research. Remarkably, reduction in anabolic processes through genetic and pharmacologic modulation of key metabolic regulators, such as PI3K, AMPK, and mTOR, extend health span across species, from flies and worms to mammals. Cellular NAD+ levels and sirtuins are also taking center stage as central players in the metabolic network that impacts aging. While dietary restriction promotes healthy aging via all of the aforementioned regulators, the larger question of how a reduction in anabolic processes downstream of these pathways leads to such beneficial effects on general physiology still remains mostly unanswered. I anticipate that two areas of research will be particularly fruitful in the near future. First, by studying the beneficial effects of brief periods of fasting, as opposed to chronic dietary restriction, we will gain a better mechanistic insight about the acute molecular and physiological effects of altered nutrient intake. Another emerging and promising line of investigation is the identification of bioactive components in the food we eat that promote healthy aging, as well as the deconvolution of their mechanisms of action. Such advances will allow for interventions that go beyond calorie restriction, such as the rational design of a new generation of “intelligent” diets.

The NAD+ Nexis

Leonard Guarente

The discovery that the anti-aging proteins, sirtuins, are NAD+-dependent deacylases suggested an intimate nexus between metabolism and aging. Studies in a variety of organisms indicate that NAD+ levels and the activity of sirtuins decline during aging, and supplementation with NAD+ precursors (nicotinamide riboside and nicotinamide mononucleotide) can raise NAD+ levels in old animals. This is associated with improved mitochondrial function, health benefits, and longer lifespan in worms and mice. When tested, these effects required the activity of sirtuins. Will the NAD+/sirtuin axis prove to be important in human health maintenance? Intervention studies are critical from a science standpoint, because other data have been uninformative or equivocal regarding any role in human aging of genetic pathways that emerged from lower organisms. In addition to NAD+ precursors, sirtuin activators are in development at GSK, and TOR inhibitors (rapamycin and its derivatives) are candidates for human trials. Metformin, which has a long and stellar history in the diabetes field, has also been proposed. Why haven’t still more compounds emerged from the field of aging research? The science is still in its adolescence and, in the case of human aging, perhaps its infancy. We may have taken but a first step in a long journey. It is nonetheless amazing that one very promising path leads to a ubiquitous small molecule that is fundamental to life and known for more than a century.

The Age Age

Brian K. Kennedy

As a PhD student, I was drawn to aging research because it was a vast unknown. Why do organisms age? Is aging truly universal? Is it modifiable? We started a yeast project, and luminaries in yeast genetics and aging research questioned the approach, arguing that a single-celled eukaryote wouldn’t tell us much about human aging. However, my interests were more driven by the belief that defining aging in a less complex setting was valuable. The work would lead to the identification of sirtuins as modulators of aging, and it was later demonstrated that pathways governing replicative aging in yeast were conserved in multicellular organisms. Now my goals are human intervention directed, and I choose to believe it is because we are living in the age of aging (rather than that I am getting older); estimates put the number of elders at over 20% of the global population by 2050. Healthcare costs are approaching incredulity, yet medical research in large part heads down the same path, developing expensive disease therapies and doing little in the way of prevention. I seek to facilitate the application of insights from aging research to extend human health span, preventing disease and extending functionality. If correct, this grand hypothesis can improve quality of life and help solve the economic crises of an ever aging population. Testing grand hypotheses should be at the forefront of academic research, especially if it offers the potential to create a major revolution in healthcare.

Understanding Healthy Aging

Eric Topol

Genomic research in medicine has thus far been predominantly focused on diseases. But we are well aware that there is marked variability in penetrance, and some people have incontrovertible pathogenic genomic variants but never manifest an abnormal phenotype. We’ve identified a very limited number of protective alleles and modifier variants to date, which is partly due to lack of focus and applying the tools that are now at hand. Our recent case-control whole-genome sequencing study of healthy aged (“Wellderly”) individuals (individuals > 85 years of age without any significant chronic medical conditions) raised the possibility that sequence variants, both rare and common, protecting against cognitive decline may play a role. Much larger samples of individuals with extreme health span are needed to understand its biologic basis; while part may be due to lifestyle and environmental factors, there is no question that omics play a role. There’s another important dividend of studying the genomics of healthy aging. Until now the reference human genome has been a collection of young people without any phenotype. This represents a significant shortcoming for such an important biomedical research anchor. By establishing a new reference human genome of healthy aging, we will be able to facilitate case-control studies of late-onset diseases.

Death Is Healthy

Tamas L. Horvath

It is inevitable that we will all die. Nevertheless, beating death has been the preoccupation of human kind from its earliest existence until today. While various and dynamic, at any given time socially acceptable facades have been provided to justify why this battle needs to be fought, the fundamental intrigue originates from the fact that nobody wants to die. Despite this selfish and biologically unsustainable greed, the impact of this quest has been providing sometimes remarkable and useful ideas of how disease of the body can be attended and perhaps cured. In my view, however, one of the most critical issues is to determine how newly gained knowledge can be utilized to benefit any given subject. Considering the biological complexity of individual faith, highly controlled experiments using model systems, including volunteer human cohorts, provide virtually no assurance that a subject will benefit from any intervention or chemical treatment when it comes to health or lifespan. Each and every subject will represent an n of 1, and the result will emerge at the time of death; thus, there is no option for adjustment. Nevertheless, in my view, the overall impact of aging research on the population and society at large can only be beneficial as long as the implementation of any new information will be to enhance the conceptual framework of medicine rather than insinuating the benefits of interventions.

The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research.

Mutations resulting in reduced signaling of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis are associated with increased life- and healthspan across model organisms. Similar findings have been noted in human cohorts with functional mutations in the somatotropic axis, suggesting that this pathway may also be relevant to human aging and protection from age-related diseases. While epidemiological data indicate that low circulating IGF-1 level may protect aging populations from cancer, results remain inconclusive regarding most other diseases. We propose that studies in humans and animals need to consider differences in sex, pathway function, organs, and time-specific effects of GH/IGF-1 signaling in order to better define the role of the somatotropic axis in aging. Agents that modulate signaling of the GH/IGF-1 pathway are available for human use, but before they can be implemented in clinical studies that target aging and age-related diseases, researchers need to address the challenges discussed in this Review.

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging.

Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. This review discusses recent developments in our understanding of how mTOR signaling is regulated by nutrients and the role of the mTOR signaling pathway in key metabolic tissues. Finally, we discuss the molecular basis for the negative metabolic side effects associated with rapamycin treatment, which may serve as barriers to the adoption of rapamycin or similar compounds for the treatment of diseases of aging and metabolism.

As the first and most direct process influencing the proteostasis capacity of a cell, regulation of translation influences lifespan across taxa. Here we highlight some of the newly discovered means by which translational regulation affects cellular proteostasis, with a focus on mechanisms that may ultimately impinge upon the aging process.

From Ancient Pathways to Aging Cells-Connecting Metabolism and Cellular Senescence.

Cellular senescence is a complex stress response that permanently arrests the proliferation of cells at risk for oncogenic transformation. However, senescent cells can also drive phenotypes associated with aging. Although the senescence-associated growth arrest prevents the development of cancer, and the metabolism of cancer cells has been studied in depth, the metabolic causes and consequences of cellular senescence were largely unexplored until recently. New findings reveal key roles for several aspects of cellular metabolism in the establishment and control of senescent phenotypes. These discoveries have important implications for both cancer and aging. In this review, we highlight some of the recent links between metabolism and phenotypes that are commonly associated with senescent cells.

Sex differences in longevity can provide insights into novel mechanisms of aging, yet they have been little studied. Surprisingly, sex-specific longevity patterns are best known in wild animals. Evolutionary hypotheses accounting for longevity patterns in natural populations include differential vulnerability to environmental hazards, differential intensity of sexual selection, and distinct patterns of parental care. Mechanistic hypotheses focus on hormones, asymmetric inheritance of sex chromosomes and mitochondria. Virtually all intensively studied species show conditional sex differences in longevity. Humans are the only species in which one sex is known to have a ubiquitous survival advantage. Paradoxically, although women live longer, they suffer greater morbidity particularly late in life. This mortality-morbidity paradox may be a consequence of greater connective tissue responsiveness to sex hormones in women. Human females' longevity advantage may result from hormonal influences on inflammatory and immunological responses, or greater resistance to oxidative damage; current support for these mechanisms is weak.

Most animals alternate periods of feeding with periods of fasting often coinciding with sleep. Upon >24 hr of fasting, humans, rodents, and other mammals enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from the prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which food consumption is restricted to certain hours of the day, allows the daily fasting period to last >12 hr, thus imparting pleiotropic benefits. Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting-mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMDs, both basic science and translational research are warranted to develop fasting-associated interventions into feasible, effective, and inexpensive treatments with the potential to improve healthspan.

Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and health span in numerous models. Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.